The immune system is a network of cells adapted to protect the organism against pathogens and cells that are not recognized as "self." Once the immune system is activated, it enlists the participation of a variety of cells and molecules to mount an effector function designed to eliminate the "non-self" entity within the body. Lymphocytes are cells of the immune system that are capable of specifically recognizing and selectively eliminating foreign entities. By contrast to other cells of the immune system, such as neutrophils which are considered non-specific in their reactions to invaders, the characteristics of lymphocytes confer specificity, diversity, memory and self/nonself recognition to the immune response.
There are two major populations of lymphocytes: B lymphocytes and T lymphocytes. B lymphocytes originate and mature within the bone marrow and are responsible for formation of antibody molecules. T lymphocytes also arise from the bone marrow but mature in the thymus. There are two major subpopulations of T-cells: T helper cells and T cytotoxic cells. The two types of T cells can be distinguished by the presence of one of two membrane glycoproteins, either CD4 or CD8. The T-helper cells (which express CD4) when activated by antigen-complexes (foreign molecules coupled to special proteins) respond by secreting various growth factors known collectively as cytokines. These cytokines are signals that activate other cells of the immune system, including the T-cytotoxic cells. The T-cytotoxic cells (which express CD8) when activated, proliferate and differentiate into cytotoxic T lymphocytes (CTL) which are able to monitor for and eliminate from the body pathogenic cells, foreign cells, virus-infected cells, and tumor cells.
The normal development, maturation and differentiation of T lymphocytes are regulated by peptide hormones secreted by thymic cells. One such hormone is the 49-amino acid residue peptide, thymopoietin. Residues 32-36 of thymopoietin, Arg-Lys-Asp-Val-Tyr, retain the biological activities of thymopoietin, and are the basis for an immunomodulatory drug called thymopentin. The therapeutic applications of thymopentin include use for rheumatoid arthritis, dermatologic conditions, infections by bacteria, virus and fungi, reversal of immune depression due to surgery or to cancer therapy, potentiation of responses to hepatitis B virus vaccination, and treatment of acquired immunodeficiency syndrome (AIDS), a condition in which T-helper (CD4) cells are specifically attacked by the virus (Christian, J. S., "A Review of the Pharmacology, Clinical Applications, and Toxicology of Thymopentin," Transgenica: The Journal of Clinical Biotechnology, 1, pp. 23-34, 1994).
A second compound with similar properties to thymopentin is the dipeptide, Glu-Trp, called thymogen. The sequence -Glu-Trp- also occurs in the molecule that is precursor for the synthesis of thymopoietin but -Glu-Trp- is not part of the 49-amino acid hormone nor is this dipeptide recognized as being a contributor to biological activity of thymopoietins. Thymogen was discovered and was used primarily in Russia for the prophylaxis and treatment of infections. Thymogen was used for the enhancement of immune function after damage of lymphocytes by accidental exposure to irradiation as a result of the Chernobyl incident. (Khavinson et al., WO 92/17191 and WO 93/08815, "Pharmaceutical Dipeptide Compositions and Methods of Use Thereof").
.gamma.-L-Glutamyl derived peptides occur naturally in the body, the most well-known example being the tripeptide glutathione. Synthetic .gamma.-L-glutamyl-molecules have also been used as candidate drugs. These candidates are called "prodrugs" because the .gamma.-L-glutamyl moiety is used as a carrier for the active portion of the molecule. For example, .gamma.-L-glutaminyl-4-hydroxy-3-iodobenzene demonstrates anti-tumor activity in human and in mouse melanoma cell lines. It is thought that the anti-tumor activities of this compound is due to enzymatic release of 4-hydroxy-3-iodobenzene near the tumor cells (Prezioso et al., ".gamma.-Glutamyltranspeptidase Expression Regulates the Growth Inhibitory Activity of the Anti-tumor Prodrug .gamma.-glutaminyl-4-hydroxy-3-iodobenzene," International Journal of Cancer, 56, pp. 874-879, 1994). Also, .gamma.-L-glutamyl-dopamine and .gamma.-L-glutamyl-5-hydroxy-tryptophan have been described as prodrugs that might carry and supply dopamine and 5-hydroxy-tryptophan to brain neurons (Likamwa et al., "The Antinatriuretic Action of .gamma.-L-glutamyl-5-hydroxy-L-tryptophan is Dependent on its Decarboxylation to 5-hydroxytroptamine in Normal Brain," British Journal of Clinical Pharmacology, 387:265-269, 1994).
PCT document WO 96/40740, published Dec. 19, 1996, inventors Deigin and Korotkov disclose peptides of formula X-A-D-Trp-Y (I), where: A=D-Glu or D-isoglutamic acid (D-iGlu); X=H, Gly, Ala, Leu, Ile, Val, Nva, Pro, Tyr, Phe, Trp, D-Ala, D-Leu, D-Ile, D-Val, D-Nva, D-Pro, D-Tyr, D-Phe, D-Trp, .gamma.-aminobutyric acid or .epsilon.-aminocaproic acid; Y=Gly, Ala, Leu, Ile, Val, Nva, Pro, Try, Phe, Trp, D-Ala, D-Leu, D-Ile, D-Val, D-Nva, D-Pro, D-Try, D-Phe, D-Trp, .gamma.-aminobutyric acid, .epsilon.-aminocaproic acid, OH, or 1-3C substituted amino. Compounds (I) are said to have immunosuppressant activity (e.g. inhibiting proliferation of spleen cells) and to be useful in human and veterinary medicine and experimental biochemistry.